The present invention relates to a method to enhance healing of sternum after sternotomy (i.e., cutting sternum to approach heart) in operations such as open heart surgery or coronary artery surgery including the sternotomy with removal of at least one of internal thoracic arteries (hereinafter sometimes referred to as xe2x80x9cITAxe2x80x9d), using an agent containing angiogenetic factor(s).
Sternotomy is almost always necessary to operate on heart with various heart disease such as coronary artery disease including myocardial infarction and its mechanical complications, valvular heart disease, aortic disease, and congenital heart disease. However, it takes time for sternum to heal and sometimes it does not heal well.
Slow or poor healing of the sternum is one of the problems after the sternotomy therefore heart surgery. Slow healing prolongs patients"" hospital stay and increases health care cost considerably, and delays patients return to work or social activity. Poor healing of the sternum is one of the serious problems after heart operations performed though a sternotomy, and often causes deep sternal wound infection that results in increased mortality and morbidity in spite of expensive intensive care. Previous studies described the risk factors for poor sternal healing as follows: obesity, chronic obstructive pulmonary disease (such as chronic bronchitis or emphysema), elderly age, peripheral vascular disease, reoperation, diabetes mellitus, use of internal thoracic artery (ITA) conduit(s), operation time, low cardiac output, mechanical ventilation time, and reexploration for bleeding. Increasing number of patients have some of above risk factors and slow/poor sternal healing will be even more problematical. Slow/poor sternal healing often limits the use of bilateral internal thoracic arteries (hereinafter sometimes referred to as xe2x80x9cBITAxe2x80x9d) in coronary bypass surgery especially in diabetic patients whose hearts are shown to benefit form BITA grafting, because diabetic patients often develop sternal necrosis (i.e., dead sternum bone) particularly after BITA removal (i.e., to make grafts for heart) due to lack of blood supply.
It has been reported that a basic fibroblast growth factor (hereinafter sometimes referred to as xe2x80x9cbFGFxe2x80x9d) is not only an intense angiogenetic (i.e., create new vessels and increase blood supply to the sternum) mitogen but also can stimulate bone formation. Other growth factors such as aFGF, VEGF, TGF xcex2 have more or less benefit in enhancing the sternal healing via their angiogenetic effects.
Some of the present inventors have already proposed to use an agent containing bFGF for treating bone disease in EP-A-0 493 737 and a cross-linked gelatin gel preparation containing bFGF in EP-A-0 702 959. That is, some of the present inventors have already proposed to use an agent containing bFGF for the treatment of bone diseases in EP-A-0 493 737 and a cross-linked gelatin gel preparation containing bFGF in EP-A-0 702 959. In EP-A-0 493 737, a novel agent for the treatment of bone diseases such as various traumatic fractures, various fatigue fractures, pathologic fractures including fracture accompanied by osteoporosis, osteomalacia, malignant tumor, multiple myeloma, etc., reduction in bone strength accompanied by various diseases as mentioned above, and inhibition of bone formation accompanied by various diseases as mentioned above. In EP-A-0 702 959, there is disclosed a hemoglobin level increasing effect, a bone mineral content increasing effect, and the like. They have demonstrated that gelatin hydrogels which incorporated bFGF enhanced the in vivo angiogenetic effect and bone regeneration.
Moreover, some of the present inventors have reported in xe2x80x9cJ. Neurosurg., Vol. 86, pp. 871-875 (1997)xe2x80x9d potential efficacy of bFGF incorporated in biodegradable hydrogels for skull bone regeneration using a rabbit model and in xe2x80x9cBiomaterials, vol. 19, pp. 807-815 (1998)xe2x80x9d bone regeneration by bFGF complexed with biodegradable hydrogels of skull bone defects which has been clinically recognized as almost impossible. However, in either of the above-mentioned references, there is no description about healing of sternum after sternotomy including the sternotomy with ITA removal. Sternum has a different shape and blood supply (i.e., different feeding arteries) from that of the skull bone or long bones; the difference is more obvious after sternotomy (i.e., almost always longitudinal cut rather than transverse cut).
An object of the present invention is to provide a method to enhance healing of the sternum after sternotomy including the sternotomy with the BITA removal, which can shorten patients"" hospitalization and can decrease complications related to poor sternal healing, and therefore will reduce health care cost, will facilitate patients"" return to work and will help increase their productivity. The present invention can effectively heal the sternum by using an agent containing angiogenetic or osteogenetic factor(s).
In an attempt to conquest the problem of slow or poor sternal healing after sternotomy, the present inventors have developed a few methods to enhance sternal healing as described below. In short, the present invention applies one or more of the above angiogenetic factors or their gene to the sternum or the tissue around to enhance angiogenesis in order to offset the shortness of blood supply for the sternum or to help osteogenesis (i.e., help create bone tissue for the sternum) to stabilized the sternum and help sternal healing.
That is, the present invention relates to a method to enhance healing of or treating sternum after sternotomy with or without removal of at least one of thoracic arteries which comprises applying an agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
The present invention also relates to a method of regenerating bone at sternum after sternotomy or sternotomy with or without removal of at least one of internal thoracic arteries which comprises applying an agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
The present invention further relates to a method of subjecting to vascularization around sternum after sternotomy or sternotomy with or without removal of at least one of internal thoracic arteries which comprises applying an agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
Moreover, the present invention relates to a method of treating a fracture site after sternotomy with or without removal of at least one of internal thoracic arteries which comprises applying an agent for the treatment of the fracture site after sternotomy in direct contact with the fracture site of a rib, cartilage or their junction, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
Also, the present invention relates to an agent to enhance healing of or treating sternum after sternotomy with or without removal of at least one of thoracic arteries by applying the agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
The present invention also relates to an agent of regenerating bone at sternum after sternotomy or sternotomy with or without removal of at least one of internal thoracic arteries by applying the agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
The present invention further relates to an agent of subjecting to vascularization around sternum after sternotomy or sternotomy with or without removal of at least one of internal thoracic arteries by applying the agent for the treatment of sternum after sternotomy to or at around the sternum, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.
Moreover, the present invention relates to an agent of treating a fracture site after sternotomy with or without removal of at least one of internal thoracic arteries by applying an agent for the treatment of the fracture site after sternotomy in direct contact with the fracture site of a rib, cartilage or their junction, wherein said agent comprises at least one selected from the group consisting of an angiogenetic factor, an osteogenetic factor and their analogues as an effective ingredient.